Activation of the multicomponent antigen receptor in T cells (TCR) results in rapid activation of a protein tyrosine kinase pathway. To fully understand the function of this pathway, the kinase and its substrates must be characterized. We have previously shown that the protein tyrosine kinase p60fyn is associated with the TCR. Further evidence that this kinase is involved in T cell activation is our observation that it is also associated with the GPI-linked glycoprotein Thy-1, another molecule involved in T cell activation. Another candidate for a TCR-protein tyrosine kinase is a 70kD protein that binds to the activated TCR and becomes tyrosine phosphorylated. Evidence that this protein binds ATP suggests that it itself is a protein tyrosine kinase that binds the TCR. One substrate for tyrosine kinases activated by the TCR is the 100kD valosin-containing protein (VCP). This protein is the mammalian homologue of cdc48p, a yeast protein required for progression through the cell cycle. We have stably expressed this protein in T cells and confirmed that it is a tyrosine kinase substrate. The protein exists as a hexamer in the cytosol. Current studies are addressed at determining the function of this protein with or without tyrosine phosphorylation. Abnormal tyrosine phosphorylation of substrates has been detected in T cells that are infected with human immunodeficiency virus (HIV). These phosphorylation can also be detected in cell lines that express HIV envelope proteins after engagement of the CD4 molecule. The kinetics of phosphorylation of these substrates corresponds to syncytia formation. Inhibition of tyrosine phosphorylation with the tyrosine kinase inhibitor, herbimycin, results in inhibition of substrate phosphorylation, syncytia formation and cell death.